Anti-idiotypic antibodies to anti-HLA receptors induced by pregnancy

We have previously shown that lymphoblasts alloactivated in vitro acquire the capacity of stimulating the autologous mixed lymphocyte response. This response is anti-idiotypic in nature because lymphocytes so primed display accelerated memory responses only when restimulated by autologous lymphoblasts that have been alloactivated against the same HLA-DR antigen. Based on this observation we have postulated that the absence of HLA antibodies in alloimmunized human subjects may be due to the development of autoantibodies that react with the anti-HLA receptors expressed by primed lymphocytes or by anti-HLA antibodies or both. This hypothesis has been confirmed in the present investigations which show that sera from parous women react with autologous T lymphoblasts primed in 5-day mixed lymphocyte culture against their husband—i.e., with lymphoblasts expressing receptors for the immunizing donor. Anti-HLA receptors expressed by T and B lymphocytes seem to share serologic determinants because sera that bind to autologous alloactivated lymphoblasts are also capable of inhibiting the anti-HLA activity of autologous and homologous sera. Auto-anti-idiotypic antibodies inhibit the autologous mixed lymphocyte response to autologous alloactivated lymphoblasts, a phenomenon whose in vivo correlate may reside in autoinhibition of anti-HLA antibody formation and of allograft immunity. Because auto-anti-idiotypic antibodies were found in sera from all parous women tested, the hypothesis that nonresponsiveness to alloantigens exists as a state per se is not likely. The passive transfer of antireceptor (idiotype) immunity by use of antibodies from pregnant women's sera may provide a powerful tool for specific suppression of allograft rejection.     

Dynamic PET/CT imaging of 18F-(2S, 4R)4-fluoroglutamine in healthy volunteers and oncological patients

European Journal of Nuclear Medicine and Molecular Imaging - The purpose of this study was to compare dynamic 18F-FGln PET/CT images of healthy subjects and cancer patients and explore the best...     

Childhood insulinoma masquerading as seizure disorder

A 9 year old girl presented with seizures, weight gain and early morning behavioural changes. She had been commenced on anticonvulsants and was subsequently diagnosed with hyperinsulinaemic hypoglycaemia. This case demonstrates the importance of blood glucose monitoring in children presenting with new‐onset seizures and/or with early morning or fasting behavioural changes, the challenges in localizing the lesion, as well as the difficulties in achieving normoglycaemia prior to, and immediately following, surgery.     

Evaluation of serum anti-mullerian hormone as a biomarker of early ovarian aging in young women undergoing IVF/ICSI cycle

Objective: To determine whether or not the level of serum anti-Müllerian hormone (AMH) is related to early ovarian aging in young women (< 35 years of age) undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles. Design: Retrospective cohort study. Setting: An IVF laboratory in a university hospital in Taiwan. Patient (s): 70 young women (< 35 years of age) with low level of serum AMH (< 2 ng/ml) and 104 young women with level of serum AMH (≥ 2 ng/ml) who underwent IVF/ICSI cycles between January 2011 and November 2012 were enrolled. Intervention (s): None. Main outcome measure (s): Number of oocytes, fertilization rate, embryo quality, cycle cancellation rate, clinical pregnancy/abortion rate, and perinatal/infant outcomes. Results: The clinical pregnancy rate per transfer was favorable (low AMH group vs. normal AMH group [47.2% and 47.9%]) for women < 35 years of age, including women with a low serum AMH. Similarly, the live birth rate per transfer (low AMH group vs. normal AMH group [37.7% and 35.4%]) and perinatal outcomes were also comparable between the two groups. A significantly higher cycle cancellation was noted in the low AMH group than the normal AMH group (24.2% vs. 7.6%). Conclusion: Although early ovarian aging should be taken into consideration for young and infertile women with low AMH level than expected, our results suggest that low serum AMH level may suggest early ovarian aging in accelerated oocyte loss only, but may not fully represent “early ovarian aging” based on the favorable outcomes of pregnancy.     

Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption

Objectives

Primary failure of tooth eruption (PFE) is a rare autosomal-dominant disease characterized by severe lateral open bite as a consequence of incomplete eruption of posterior teeth. Heterozygous mutations in the parathyroid hormone 1 receptor (PTH1R) gene have been shown to cause PFE likely due to protein haploinsufficiency. To further expand on the mutational spectrum of PFE-associated mutations, we report here on the sequencing results of the PTH1R gene in 70 index PFE cases.

Materials and methods

Sanger sequencing of the PTH1R coding exons and their immediate flanking intronic sequences was performed with DNA samples from 70 index PFE cases.

Results

We identified a total of 30 unique variants, of which 12 were classified as pathogenic based on their deleterious consequences on PTH1R protein while 16 changes were characterized as unclassified variants with as yet unknown effects on disease pathology. The remaining two variants represent common polymorphisms.

Conclusions

Our data significantly increase the number of presently known unique PFE-causing PTH1R mutations and provide a series of variants with unclear pathogenicity which will require further in vitro assaying to determine their effects on protein structure and function.

Clinical relevance

Management of PTH1R-associated PFE is problematic, in particular when teeth are exposed to orthodontic force. Therefore, upon clinical suspicion of PFE, molecular DNA testing is indicated to support decision making for further treatment options.     

Short Communication New 5-HT1A receptor antagonist: [3H]p-MPPF

A new 5-HT_1A receptor antagonist ligand, [³H]p-MPPF, 4-(2′-methoxy-)-phenyl-1-[2′-(N-2′-pyridyl)-p-fluorobenzamido]ethyl-piperazine, was prepared and characterized. It demonstrated high affinity and selectivity toward 5-HT_1A receptors (K_d = 0.34 ± 0.12 nM and B_max = 145 ± 35 fmol/mg protein in rat hippocampal membrane homogenates). The binding is not sensitive to 100 μM Gpp(NH)p. Initial autoradiography studies of rat brain sections exhibit regional localization consistent with the known 5-HT_1A receptor distribution. This potential 5-HT_1A antagonist ligand may provide a powerful tool for 5-HT_1A receptor pharmacology studies in the central nervous system. © 1996 Wiley-Liss, Inc.     

Incidence and risk factors for pulmonary mycosis in kidney transplantation

IntroductionPulmonary mycosis, a severe complication following kidney transplantation, is associated with a high rate of mortality. The incidence of and independent risk factors for its development have not been well studied.MethodsWe retrospectively reviewed 2573 kidney transplant recipients. Patients were divided into case and control groups based on a diagnosis of pulmonary mycosis. The recipient baseline characteristics, posttransplant complications, immunosuppressive regimens and antibiotic usages were analyzed to identify independent risk factors.ResultsThe total incidence of pulmonary mycosis among kidney recipients was 2.1%. Upon univariate analysis, patients in the case group differed significantly from the controls based upon: older age, higher retransplantation rate, longer dialysis time, induction with ATG or anti-CD25 monoclonal antibodies, maintenance treatment with FK506 or MMF, broad-spectrum antibiotics, higher incidences of acute rejection episodes, DGF, impaired liver function, leukopenia, cytomegalovirus infection, and delayed incisional healing (P < .05). Multivariate analysis showed that older age, retransplantation, ATG induction, FK506/MMF, broad-spectrum antibiotics, leukopenia, and delayed incisional healing were independent risk factors for pulmonary mycosis.ConclusionsThe use of more potent immunosuppressive regimens seems to increase the rate of pulmonary mycosis. Patients who have five or more independent risk factors are at high risk for developing pulmonary mycosis.     

An assessment of drug information sheets for diabetic patients: only active involvement by patients is helpful

Insulin/sulphonylurea-treated diabetics attending a busy university diabetic clinic were studied to determine whether issuing drug information sheets and/or age influenced understanding and behaviour regarding their disease and its treatment, especially with respect to avoiding hypoglycaemia. Patients were each asked 10 basic questions (each correct answer scoring 1), stratified by age (20 were less than or equal to 45 years and 91 greater than 45 years). According to a single-blind randomised protocol, they were issued or not issued with drug information sheets (providing information to correctly answer all 10 questions). After 2-3 months, 107 (88 aged greater than 45 years) were retested and asked whether they recalled an information sheet, read it themselves or had it read to them. Whether or not patients received sheets, corresponding mean aggregate scores were very similar in both age groups and there was no correlation with age. Second test scores yielded clinically and statistically significant increments in both the sheet and no sheet groups, respective mean aggregate scores increasing from 4.48 to 5.80 and 5.14 to 6.27 (P less than 0.001). Among patients issued with sheets, 32 who recalled reading them achieved the greatest improvement in mean scores (4.53 to 6.16, P less than 0.001). Active interaction/communication (participation in first test, recall and reading of information sheet) had a favourable educational impact irrespective of age, but merely issuing drug information sheets had no benefit.     

Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells

An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML.